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Gene therapy in advance curbs heart damage

3 August 2004

By Michael Le Page

Gene therapy could be given in advance to protect high-risk patients from the consequences of suffering a stroke or heart attack, suggests a new study.

A team at Brigham and Women’s Hospital in Boston, US, and Queen’s University in Ontario, Canada, have shown that animals equipped with an extra gene can survive simulated heart attacks virtually unscathed. The gene switches on quickly in conditions of low oxygen and saves cells from death.

Strokes and heart attacks occur when blockages in the arteries supplying the brain or heart muscles cut off the supply of blood to tissues. The resulting lack of oxygen kills cells, often leaving people with permanent damage, if they survive.

Cells do have ways of protecting themselves when oxygen levels are low. They switch on the genes for a number of protective proteins, including heme oxygenase-1. But the researchers found that it takes 12 hours or more for cells to produce high levels of HO-1, by which time it is too late.

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If cells could be coaxed to produce more HO-1 faster, the researchers reasoned, the cells might be saved during a stroke or heart attack. So they modified an adeno-associated virus to deliver an extra HO-1 gene to cells.

Blood supply

The HO-1 protein produced by the gene is identical to the natural human protein. The difference is that the added gene has multiple copies of the switch, or promoter sequence, that turns on protein production.

The extra gene makes no difference normally, but when oxygen levels fall, more HO-1 is produced more quickly. Experiments in the lab show that cells with the extra gene produce high levels of HO-1 within an hour of oxygen levels plummeting.

Next, the team injected the virus into the heart, liver or muscle tissue of rats and then cut off the blood supply to these tissues for up to an hour. “The level of protection was dramatic,” says team member Victor Dzau, now at Duke University in North Carolina. More recent tests show the approach can also protect brain cells, he told New Scientist.

Bacterial infections

There are already drugs that can be given to patients who suffer heart attacks or strokes to help reduce cell death, Dzau says. But the trouble with this approach is that there is only a narrow window of time when these drugs can make a difference.

By the time people reach a hospital and are diagnosed, it is often too late. Giving high-risk patients gene therapy in advance, by contrast, would ensure that the protective mechanism kicks in as soon as it is needed.

The researchers believe the approach has broad applications. Besides people who have a high risk of having a stroke or heart attack, the therapy could also help patients with injuries, shock or bacterial infections, which can reduce the blood supply to some tissue or organs, they point out. It could also be given to patients prior to complicated operations. If necessary, more genes could be added to the virus to provide even better protection.

The team now plans to test the gene therapy on larger animals such as pigs. “We are convinced this strategy is going to be effective,” says Dzau.

Journal reference&colon; Proceedings of the National Academy of Sciences (DOI&colon; 10.1073/pnas.0404616101)